The compound represented by formula (I):
is disclosed in, for example, JP 6-56873 A (WO93/24509) and JP 9-100291 A (WO97/06177). This compound is known to have the ability to enhance the movement of the digestive tract.
The preparation of this compound is disclosed in, for example, JP 9-100291 A, Bioorg. & Med. Chem. Lett. vol. 4(11), 1347 (1994) and JP 9-100291 A.
Conventionally, there are three patterns for crystals of a fumarate salt of compound (I): A-type crystal (hereinafter simply referred to as “A-type crystal”), C-type crystal (hereinafter simply referred to as “C-type crystal”) and D-type crystal (hereinafter simply referred to as “D-type crystal”). Each of the A-type, C-type and D-type crystals is disclosed in JP 9-100291 A and can be prepared as described in this publication.
The A-type crystal may be prepared from a fumarate salt of compound (I) through recrystallization from a mixed solvent of methanol and isopropanol. The molar ratio between compound (I) and fumarate is 2:1. The A-type crystal provides the diffraction pattern as shown in FIG. 1 when measured by X-ray diffractometry with Cu—Kα radiation.
The C-type crystal may be prepared from a fumarate salt of compound (I) through treatment with ethyl acetate. The molar ratio between compound (I) and fumarate is 1:1. The C-type crystal provides the diffraction pattern as shown in FIG. 2 when measured by X-ray diffractometry with Cu—Kα radiation.
The D-type crystal may be prepared from a fumarate salt of compound (I) through treatment with a mixed solvent of ethyl acetate and water. The molar ratio between compound (I) and fumarate is 2:1. The D-type crystal provides the diffraction pattern as shown in FIG. 3 when measured by X-ray diffractometry with Cu—Kα radiation.
Among the A-type, C-type and D-type crystals, the D-type crystal is reported to have high quality as a pharmaceutical and a starting material therefor because it is superior in stability or other properties to the other crystals (JP 9-100291 A).
However, the prior art D-form crystal prepared by the conventionally known techniques as mentioned above which involve the following problems: a large volume of crystallization solvent remains in the crystal as a residual solvent; the residual solvent is difficult to remove during drying procedure; and the dryness of residual solvent cannot be below 1500 ppm. In this case, the residual solvent remaining in the D-form crystal is ethyl acetate, which is less toxic and less risky for human health (see “Guideline for residual solvents in pharmaceuticals” attached to the Notification No. 307 of Mar. 30, 1998 delivered from the director of Evaluation and Licensing Division, Pharmaceutical and Medical Safety Bureau, Ministry of Health and Welfare, Japan). However, it is naturally more desirable to reduce the content of such a less toxic solvent remaining in the crystal in a case where the crystal is intended to be used as a starting material for pharmaceuticals. Preferably, the content of residual solvent should be reduced to 1500 ppm or below, more preferably 1000 ppm or below. The prior art D-form crystal also involves another problem of having a small particle size, which often leads to tabletting troubles during the preparation of tablets comprising this crystal.